Abstract
Chiral Brønsted acids (proton donors) have been shown to facilitate a broad range of asymmetric chemical transformations under catalytic conditions without requiring additional toxic or expensive metals1,2,3,4,5,6,7,8. Although the catalysts developed thus far are remarkably effective at activating polarized functional groups, it is not clear whether organic Brønsted acids can be used to catalyse highly enantioselective transformations of unactivated carbon–carbon multiple bonds. This deficiency persists despite the fact that racemic acid-catalysed ‘Markovnikov’ additions to alkenes are well known chemical transformations. Here we show that chiral dithiophosphoric acids can catalyse the intramolecular hydroamination and hydroarylation of dienes and allenes to generate heterocyclic products in exceptional yield and enantiomeric excess. We present a mechanistic hypothesis that involves the addition of the acid catalyst to the diene, followed by nucleophilic displacement of the resulting dithiophosphate intermediate; we also report mass spectroscopic and deuterium labelling studies in support of the proposed mechanism. The catalysts and concepts revealed in this study should prove applicable to other asymmetric functionalizations of unsaturated systems.
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Acknowledgements
We are grateful to D. Benitez and E. Tkatchouk (Goddard Group, California Institute of Technology) for performing DFT calculations, to U. Anderson and T. Iavarone of the QB3/Chemistry Mass Spectrometry Facility, and to A. DiPasquale of the X-ray Crystallography Facility. We acknowledge funding from the Director, Office of Science of the US Department of Energy (contract no. DE-AC02-05CH11231) and from NIHGMS (R01 GM074774). V.R. is grateful for a Natural Sciences and Engineering Research Council of Canada (NSERC) postdoctoral fellowship. G.L.H. is grateful for a Bristol-Myers/Squibb graduate fellowship.
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N.D.S. initiated the hydroamination study. V.R. optimized the catalysts and initiated the hydroarylation study. N.D.S., V.R., G.L.H. and J.W. performed the experiments. N.D.S., G.L.H. and F.D.T. developed the mechanistic concepts. G.L.H. and N.D.S. wrote the manuscript with input from all authors.
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X-ray crystallographic data have been deposited in the Cambridge Crystallographic Data Centre database (http://www.ccdc.cam.ac.uk/) under code CCDC 800545.
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The file contains Supplementary Figures 1-11 with legends, Supplementary Table 1, additional references and Supplementary data (Copies of NMR and HPLC spectra). (PDF 5334 kb)
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Shapiro, N., Rauniyar, V., Hamilton, G. et al. Asymmetric additions to dienes catalysed by a dithiophosphoric acid. Nature 470, 245–249 (2011). https://doi.org/10.1038/nature09723
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DOI: https://doi.org/10.1038/nature09723
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